ABSTRACT
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Haemophilus influenzae/drug effects , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Administration, Oral , Animals , Antifungal Agents/pharmacology , Aspergillus/drug effects , Aza Compounds/chemistry , Aza Compounds/pharmacology , Glycosides/chemistry , Indenes , Injections, Intravenous , Mice , Microbial Sensitivity Tests , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Aldehydes/chemical synthesis , Aldehydes/chemistry , Aldehydes/pharmacology , Alkylation , Diterpenes , Fungi/drug effects , Hydrolysis , Indicators and Reagents , Microbial Sensitivity Tests , Oxidation-Reduction , Structure-Activity RelationshipABSTRACT
Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.
Subject(s)
Antifungal Agents/metabolism , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Biotransformation , Candida albicans/drug effects , Candida glabrata/drug effects , Diterpenes , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Nocardia/metabolism , StereoisomerismABSTRACT
The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungi/drug effects , Oxazepines/chemical synthesis , Oxazepines/pharmacology , Candida albicans/drug effects , Candida glabrata/drug effects , Cryptococcus neoformans/drug effects , Hydrogen Bonding , Indenes , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.
